PL211062B1 - New pharmaceutical compositions containing flibanserin polymorph a - Google Patents

Abstract

The invention relates to oral pharmaceutical compositions containing flibanserin polymorph A , methods for the preparation thereof and use thereof as a medicament.

Description

(21) Filing number: 372457 (22) Filing date: May 19, 2003 (86) Date and number of the international application:

2003 May 19, PCT / EP03 / 005226 (87) International application publication date and number:

27.11.2003, WO03 / 97058 (11) 211062 (13) B1 (51) Int.Cl.

A61K 31/496 (2006.01) A61P 25/16 (2006.01) A61P 15/00 (2006.01) A61P 25/28 (2006.01)

A pharmaceutical composition for oral administration containing flibanserin and the use of the composition (30) Priority:

22.05.2002, EP, 02011224.9 (43) Application announced:

25.07.2005 BUP 15/05 (45) The following was announced about the grant of the patent:

April 30, 2012 WUP 04/12 (73) Authorized by the patent:

BOEHRINGER INGELHEIM PHARMA GmbH & Co. KG, Ingelheim am Rhein, DE (72) Inventor (s):

THOMAS FRIEDL, Ochsenhausen, DE GUIDO BERNHARD EDMUND RADTKE, Gau-Algesheim, DE (74) Representative:

item. stalemate. Jan Surmiak

PL 211 062 B1

Description of the invention

The invention relates to an orally administrable pharmaceutical composition containing flibanserin, and the use of such a composition.

Flibanserin as a compound 1- [2- (4- (3-trifluoromethylphenyl) piperazin-1-yl) ethyl] -2,3-dihydro-1H-benzimidazol-2-one has been disclosed in the form of its hydrochloride in European patent application EP -A-526434 and has the following chemical structure:

Flibanserin has an affinity for 5-HT1A and 5-HT2 receptors. It is therefore a promising therapeutic agent for the treatment of various diseases, for example depression, schizophrenia, Parkinson's disease, anxiety, sleep disorders, sexual and mental disorders, and age-related memory disorders.

Certain pharmaceutical activity is, of course, an essential condition for the approval of a pharmaceutically active agent. However, it also has to meet various additional requirements. These requirements relate to various parameters related to the properties of the active substance. In general, these are, for example, parameters such as the stability of the active agent under various environmental conditions, its stability during the manufacture of the pharmaceutical preparation, and the stability of the active agent in the final drug compositions. The pharmaceutically active substance used in the preparation of the pharmaceutical compositions should be as pure as possible and its stability in long-term storage has to be confirmed under various environmental conditions. It is very important to prevent the use of pharmaceutical compositions which contain, in addition to the actual active ingredient, e.g. its degradation products. In such cases, the content of the active substance in the medicaments may be lower than the specified content.

The decisive factor is the homogeneous distribution of the active substance in the preparation, especially when the drug has to be administered in small doses. To ensure a homogeneous distribution, the particle size of the active substance can be reduced to a suitable size, e.g. by grinding. Since decomposition and / or amorphization of the pharmaceutically active substance, as a side effect of milling (or micronization), should be avoided as much as possible despite the stringent conditions required during manufacture, it is very important that the active substance is very stable during milling. It is only possible to produce a homogeneous pharmaceutical preparation which will always contain a certain amount of active substance and in a reproducible manner if the active substance is sufficiently stable during grinding.

From the patent description PL 302163 (WO 93/03016) a pharmaceutical composition containing flibanserin is known, in the form of tablets, which can optionally be coated. However, the description does not specify or even suggest what type of coating should be used or what kind of properties it should have. In principle, the use of a film coating on the tablet is generally not necessary. However, if any coating film is used, it is usually to improve the palatability of the tablet or to improve its swallowing comfort. In the said document, however, nothing is mentioned about the use of a film coating a tablet for the purpose of improving the physicochemical properties of the composition or active ingredient.

Ultimately, the properties of the pharmaceutical composition as such profoundly affect the bioavailability of the active agent and thus the effectiveness of the drug in its intended therapeutic use.

The object of the invention is therefore to produce a new formulation for oral administration containing flibanserin which meets the stringent requirements of pharmaceutical compositions as mentioned above.

It has surprisingly been found that flibanserin free base in a specific polymorphic form best meets the requirements of the formulations according to the invention. This specific polymorph (polymorph A) can be obtained under certain reaction conditions which are described in more detail

PL 211 062 B1 in detail below. This polymorphic form is characterized, inter alia, by an endothermic maximum at 161 ° C, which occurs during thermal analysis using DSC (Differential Scanning Calorimetry).

The pharmaceutical composition for oral administration comprising flibanserin according to the invention is characterized in that it comprises a tablet core containing the polymorph A of flibanserin exhibiting an endothermic maximum at 161 ° C as determined by DSC in admixture with at least one pharmaceutically acceptable excipient, and further comprising a film coating the tablet core containing titanium dioxide and / or talc. Preferably, the titanium dioxide is present in an amount of 5-55 wt%, more preferably 5-50 wt%, based on the total weight of the film coating the tablet.

For the compositions according to the invention, it is preferred that the pharmaceutically acceptable excipient is a filler selected from the group consisting of lactose monohydrate, and both finely ground material and modified lactose, e.g. spray dried lactose and agglomerated lactose (Tablettose), anhydrous lactose, microcrystalline cellulose , dibasic calcium phosphate, corn starch, sugar alcohols, and mixtures thereof.

In the pharmaceutical composition according to the invention, the polymorph A of flibanserin is present in an amount of from 1 to 50% by weight, based on the total weight of the core. Preferably, the core comprises a filler in an amount of 50 to 99% by weight, based on the total weight of the core. It is also preferred that the core further comprises a binder selected from the group consisting of povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, corn starch, and mixtures thereof, and preferably the core further comprises a disintegrant selected from sodium starch glycolate, crospovidone, croscarmellose. sodium carboxymethyl cellulose, dehydrated corn starch, and mixtures thereof. The core may furthermore preferably contain antistatic agents, lubricants and release modulating agents, or release agents selected from the group consisting of silicon dioxide, talc, magnesium stearate, and mixtures thereof.

In the pharmaceutical composition of the invention, the core coating film preferably comprises at least one film former selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and polyethyl acrylate / methyl methacrylate.

The use of a composition as defined in the invention is characterized in that it is used in the manufacture of a medicament for the treatment of diseases selected from the group consisting of depression, schizophrenia, Parkinson's disease, anxiety, sleep disorders, sexual and mental disorders, and memory disorders associated with with age. Most preferably it is used in the manufacture of a medicament for the treatment of a decreased sex drive disorder.

When lactose is used as filler in the composition in the form of lactose monohydrate, it is in the form of a finely ground material (e.g., 200 mesh).

When hydroxypropyl methylcellulose (HPMC) is used as the binder, the HPMC polymers USP2910 (US Pharmacopeia) and USP2208 are particularly preferred, such as for example Methocel E5, E4M, E15M, (K15M, and K100M) supplied for example by the Dow Chemical Company. In the abbreviations mentioned above, E refers to USP2910, while K refers to USP2208. A numerical designation refers to the viscosity in a 2% aqueous solution (e.g. 5 is a viscosity of 5 cps; 15 M is a viscosity of 15,000 cps).

Based on the total weight of the core of the inventive coated tablets, the filler is preferably present in an amount of 50 to 99% by weight, preferably 55 to 95% by weight, particularly preferably about 60 to 90% by weight. It is particularly preferred that the proportion of the total amount of filler is between 65 and 85% by weight, more preferably between 68 and 80% by weight, based on the total weight of the core.

In formulations according to the invention containing a mixture of lactose monohydrate and microcrystalline cellulose as fillers (or pharmaceutically acceptable excipients), the ratio of lactose monohydrate to microcrystalline cellulose is e.g. in the range of about 15: 1 to about 1: 5, preferably in the range of about 10 : 1 to about 1: 3, more preferably about 6: 1 to about 1: 1.

If the formulations according to the invention contain a mixture of lactose monohydrate, microcrystalline cellulose and HPMC as fillers / binders (or pharmaceutically acceptable excipients), the amount of lactose monohydrate is e.g. in the range 50 to 95% by weight, preferably 60 to 90% by weight, more preferably about 65 to 85% by weight based on the total weight of filler / binder used in preparing the core. In a special solution

These tablet formulations contain lactose monohydrate in an amount of about 70 to 80% by weight based on the total weight of the filler / binder used to prepare the core. In particular formulations according to the invention, containing a mixture of lactose monohydrate, microcrystalline cellulose and HPMC as fillers / binders (or pharmaceutically acceptable excipients), the amount of microcrystalline cellulose is e.g. in the range 5 to 45% by weight, preferably 15 to 35% by weight, more preferably about 20 to 30% by weight based on the total weight of the filler / binder used to prepare the core. In a particular embodiment, these tablet formulations contain about 22 to 28% by weight of microcrystalline cellulose based on the total weight of the filler / binder used to prepare the core. In particular formulations according to the invention, containing a mixture of lactose monohydrate, microcrystalline cellulose and HPMC as fillers / binders (or pharmaceutically acceptable excipients), the amount of HPMC is e.g. in the range 0.5 to 5% by weight, preferably 1.0 to 4. , 5% by weight based on the total weight of the filler / binder used to prepare the core. In a particular embodiment, these tablet formulations contain HPMC in an amount of about 1 to 3% by weight based on the total weight of the filler / binder used to prepare the core.

When disintegrants are used in the composition of the present invention, the amount used, based on the total weight of the core of the coated tablets, is, for example, from about 0.1-10% by weight, preferably from about 0.5-5% by weight, more preferably from about 1-3% by weight. % by mass.

The core of the coated tablets according to the invention may also contain antistatic substances as additional ingredients. Antistatic agents within the scope of the invention include, for example, silicon dioxide, talc, magnesium stearate, and mixtures thereof. According to the invention, silicon dioxide is preferably used, particularly preferably in a colloidal, highly dispersed form. If the above-mentioned antistatic substances are used, their amount by weight, based on the total weight of the core of the coated tablets according to the invention, is preferably from about 0.1 to 5% by weight, preferably from about 0.3 to 2% by weight, more preferably between 0.4 and 2% by weight. 1.5% by mass.

The core of the coated tablets according to the invention may also contain antistatic agents, lubricants and release modulating or anti-sticking agents as other ingredients. These include, within the scope of the invention, e.g., stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, glycerol tribehenate, talc, and mixtures thereof. According to the invention, stearic acid and magnesium stearate are preferably used. If one or more of the aforementioned components are used, their amount by weight is preferably from about 0.01-5% by weight, preferably from about 0.05-3% by weight, particularly preferably about 0.1-2% by weight, based on the total weight. the core of the film-coated tablets. Preferably, especially in the case of magnesium stearate, the amount is about 0.2-1.5% by weight based on the total weight of the core of the coated tablets.

The film coating the core of the coated tablets according to the invention comprises at least one or more film-forming agents selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and poly (ethyl acrylate) / methyl methacrylate, the latter in the form of e.g. for example, Eudragit RL 30 D or Eudragit E 12.5 can be used. The above ingredients can optionally also be used in the form of mixtures thereof. Preferred binders are hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose and hydroxyethyl cellulose, of which hydroxypropyl methyl cellulose and hydroxypropyl cellulose are particularly preferred as film formers according to the invention. The above-mentioned binders can be used as such or in the form of mixtures thereof. In this context, according to the invention, if only one of the above-mentioned binders is used, hydroxypropyl methylcellulose is of particular importance. The amount by weight of film-forming agents, based on the total weight of the film of the coated tablets according to the invention, is preferably from about 20-95% by weight, preferably 30-90% by weight.

The core coating film may contain emulsifiers and / or plasticizers such as, for example, polyethylene glycol, glycerol and propylene glycol, optionally in the form of mixtures thereof. Preferably, polyethylene glycols are used as plasticizers. Without limiting the scope of the invention, polyethylene glycol 400 and polyethylene glycol 6000 are examples of particularly preferred polyethylene glycols. In the description of the invention, references to the term Macrogol are understood to refer to the term polyethylene glycol. The values of 400 and 6000 mentioned previously herein represent the average molecular weight of the polyethylene glycols used. The amount of plasticizer by weight, based on the total weight of the film of the coated tablets according to the invention, is preferably from about 1 to 50% by weight, preferably from 5 to 40% by weight, particularly preferably from 10 to 30% by weight. Preferably, the amount of plasticizer is about 10-25% by weight, more preferably about 12-18% by weight, based on the total weight of the film of the coated tablets.

The film coating of the coated tablets according to the invention may also contain substances with added dyes and colorants. There may be mentioned, for example, iron oxide, titanium dioxide, talc and mixtures thereof. In the case where talc is used, the amount is, for example, from about 5-50% by weight, preferably 10-40% by weight, particularly preferably 15-30% by weight, based on the total weight of the film of the coated tablets. Preferably, the amount of talc is in the range of about 15-20% by weight based on the total weight of the film of the coated tablets. In the case where titanium dioxide is used, the amount is, for example, from about 5-55% by weight, preferably 10-40% by weight, particularly preferably 15-35% by weight, based on the total weight of the film of the coated tablets. Preferably the amount of titanium dioxide is about 20-30% by weight based on the total weight of the film of the coated tablets. In the case where iron oxide is used, the amount is e.g. from about 0.1-5% by weight, preferably about 0.25-3% by weight, more preferably about 0.5-1.5% by weight based on the total weight. film-coated tablets.

In a particularly preferred embodiment, the film covering the tablet core of the invention comprises hydroxypropyl methylcellulose, polyethylene glycol and titanium dioxide. In another embodiment of the invention, the film covering the core of the inventive tablet comprises hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide and talc. In yet another embodiment of the invention, the film covering the tablet core comprises hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, talc and iron oxides, preferably red iron oxide.

The pharmaceutical composition according to the invention can be prepared according to the procedure detailed in the experimental section of this patent application.

In view of the pharmaceutical efficacy of flibanserin, the invention further relates to the use of formulations containing the polymorph A of flibanserin according to the invention as medicaments.

This is particularly true for the use of preparations containing the polymorph A of flibanserin as medicaments for the treatment of diseases in which the use of compounds with affinity for 5-HT1A and 5-HT2 receptors may be therapeutically beneficial.

In particular, the use of preparations containing the polymorph A of flibanserin are drugs for the treatment of sex drive disorders.

In particular, the use of formulations containing the polymorph A of flibanserin according to the invention includes drugs for the treatment of disorders selected from the group consisting of decreased sex drive disorders, loss of sex drive, lack of sex drive, decreased sex drive, suppressed sex drive, loss of libido, libido disorders and frigidity.

A particular use of the formulations containing the polymorph A of flibanserin according to the invention includes drugs for the treatment of disorders selected from the group consisting of low sex drive disorders, loss of sex drive, lack of sex drive, decreased sex drive, suppressed sex drive, and in particular drugs for the treatment of low sex drive disorders and loss of sex drive.

The aforementioned therapeutic effects of the preparations containing the polymorph A of flibanserin according to the invention can be achieved in men and women. However, more preferred is the use of formulations containing the polymorph A of flibanserin according to the invention for the treatment of female sexual dysfunction.

The beneficial therapeutic effects of the formulations containing the flibanserin polymorph A of the invention can be observed regardless of whether the disorder has been lifelong or acquired, and regardless of its cause (organic - both physical and drug induced, psychogenic, and a combination of organic - both physical) causes. as well as drug induced and psychogenic or unknown causes).

The following examples describe the invention. These examples reveal some preferred embodiments of the invention. However, the scope of the invention is not limited to the following disclosed examples.

Synthesis of polymorph A flibanserin:

375 kg of 1 - [(3-trifluoromethyl) phenyl] -4- (2-chloroethyl) piperazine were placed in a reactor with 2500 kg of water and 200 kg of 45% aqueous sodium hydroxide solution. While stirring, 169.2 kg of 1- (2-propenyl) -1,3-dihydrobenzimidazol-2H-one, 780 kg of isopropanol, 2000 kg of water and 220 kg of a 45% aqueous sodium hydroxide solution were added. The reaction mixture was heated to 75-85 ° C and to 6

160 kg of concentrated hydrochloric acid and 200 kg of water were added. The reaction mixture was stirred at constant temperature for about 45 minutes. After distilling a mixture of water and isopropanol (about 3000 kg), the residue was cooled to about 65-75 ° C and the pH was adjusted to 6.5-7.5 by adding 125 kg of a 45% aqueous sodium hydroxide solution. After cooling to 45-50 ° C, the pH was adjusted to 8-9 by adding about 4 kg of a 45% aqueous sodium hydroxide solution. The mixture was then cooled to 30-35 ° C and centrifuged. The residue thus obtained was washed with 340 L of water and 126 L of isopropanol, and then with water until chloride elimination. The wet product was dried under reduced pressure at about 45-55 ° C to obtain 358 kg of crude polymorph A flibanserin. The thus-obtained crude product was introduced into a reactor with 1750 kg of acetone and the resulting mixture was heated to reflux temperature while stirring. The resulting solution was filtered and the filtrate was concentrated by distillation. The temperature was maintained at 0-5 ° C for about 1 hour, then the precipitate was separated by filtration and dried at 55 ° C for at least 12 hours. The final yield is 280 kg of pure flibanserin polymorph A.

Analysis of flibanserin polymorph A:

Flibanserin polymorph A was examined by DSC (Differential Scanning Calorimetry). The peak temperature determined for polymorph A is about 161 ° C. A Mettler TA 3000 System equipped with a TC 10-A processor and a DSC 20 cell was used for DSC testing. The heating rate was 10 K / min.

Flibanserin polymorph A was further investigated by the powder X-ray diffraction method. The X-ray powder pattern for polymorph A was obtained under the following conditions:

Apparatus: Philips PW 1800/10 diffractometer equipped with a digital microvax 2000.

Set parameters: X-ray radiation

Tube type: Cu (focal length)

Wavelengths (1): Κ _α1 = 1.54060 A ka2 = 1.54439 A.

Intensity ratio (α2 / α1): 0.500 Initial angle [° 2Θ]: 2,000 End angle [° 2Θ]: 60,000 Stroke [° 2Θ]: 0.020 Maximum intensity [s]: 7310.250 Scan Type: continuous Minimum width at the end of the peak 0.00 Maximum width at the end of the peak 1.00 peak width at the base: 2.00 Minimum significance: 0.75 Number of peaks: 69 Generator: high voltage: 50 kV pipe current: 30 mA

The X-ray powder pattern obtained for polymorph A is illustrated in Fig. 1. The corresponding values are summarized in Table 1.

T a b l i c a 1:

Corner [° 2Θ] value d α1 [A] value d α2 [A] Width peak [° 2Θ] Int. peak [counts] Int. introduction [counts] Rel. int. [%] Relevance. 1 2 3 4 5 6 7 8 5.195 16.9967 17.0390 0.960 8 69 0.1 1.05 9.045 9.7689 9.7931 0.100 92 96 1.3 0.97 9.335 9.4660 9.4896 0.080 114 98 1.6 0.88 10.025 8.8160 8.8379 0.140 400 100 5.5 7.18 10.595 8.3430 8.3637 0.140 204 102 2.8 3.46 11.290 7.8309 7.8503 0.140 467 104 6.4 6.91 13.225 6.6891 6.7058 0.180 548 112 7.5 13.10 14.595 6.0642 6.0793 0.180 404 121 5.5 9.17

PL 211 062 B1 cont. table 1

1 2 3 4 5 6 7 8 15.460 5.7268 5.7410 0.140 4186 125 57.3 23.20 16.655 5.3185 5.3317 0.200 515 130 7.0 12.38 17.085 5.1856 5.1985 0.100 1347 132 18.4 2.78 17.285 5.1260 5.1388 0.060 1399 135 19.1 2.26 17.420 5.0866 5.0992 0.100 1204 135 16.5 4.71 18,140 4.8863 4.8984 0.180 1043 139 14.3 13.14 18.650 4.7538 4.7656 0.120 1063 142 14.5 0.91 19,140 4.6332 4.6447 0.140 7310 144 100.0 32.77 19.820 4.4757 4.4869 0.160 3624 146 49.6 9.02 20.080 4.4184 4.4294 0.140 5402 149 73.9 21.06 20.385 4.3530 4.3638 0.160 2652 149 36.3 23.25 21.215 4.1845 4.1949 0.160 369 154 5.0 5.78 21.890 4.0570 4.0670 0.200 773 156 10.6 3.09 22.630 3.9259 3.9357 0.280 4277 161 58.5 74.66 23,210 3.8291 3.8386 0.120 484 164 6.6 3.33 24.355 3.6516 3.6607 0.060 27.25 169 37.3 1.16 24.610 3.6144 3.6234 0.140 3540 172 48.4 17.08 24.995 3.5596 3.5684 0.100 529 174 7.2 1.01 25,260 3.5228 3.5316 0.120 557 174 7.6 3.02 26.575 3.3514 3.3597 0.240 2421 182 33.1 42.58 27.155 3.2811 3.2893 0.140 676 185 9.2 1.32 27.310 3.2629 3.2710 0.100 767 185 10.5 2.75 27.865 3.1991 3.2071 0.120 420 188 5.7 1.08 28,210 3.1608 3.1686 0.100 1467 190 20.1 0.79 28.325 3.1482 3.1560 0.140 1789 190 24.5 4.41 28.650 3.1132 3.1210 0.180 1204 190 16.5 11.65 29,520 3.0234 3.0309 0.220 1011 196 13.8 15.74 30,250 2.9521 2.9594 0.120 159 199 2.2 1.22 31.105 2.8729 2.8800 0.360 282 204 3.9 8.14 31,905 2.8026 2.8096 0.100 339 207 4.6 0.96 32.350 2.7651 2.7720 0.120 237 210 3.2 3.01 33,300 2.6884 2.6950 0.180 1347 216 18.4 14.06 33.640 2.6620 2.6686 0.100 404 216 5.5 1.45 34.880 2.5701 2.5765 0.200 202 222 2.8 1.04 35.275 2.5422 2.5486 0.240 299 225 4.1 4.84 36.055 2.4890 2.4952 0.280 202 228 2.8 3.78 36.910 2.4333 2.4393 0.320 169 234 2.3 0.90 37,160 2.4175 2.4235 0.120 216 234 3.0 2.14

PL 211 062 B1 cont. table 1

1 2 3 4 5 6 7 8 37.680 2.3853 2.3912 0.240 240 237 3.3 1.58 39.435 2.2831 2.2888 0.280 449 246 6.1 2.67 39.675 2.2698 2.2755 0.080 396 246 5.4 0.82 40.325 2.2347 2.2403 0.160 520 250 7.1 0.95 40.930 2,2031 2,2086 0.120 480 253 6.6 2.66 41,445 2.1769 2.1823 0.240 372 256 5.1 2.65 41.990 2.1499 2.1552 0.120 538 259 7.4 1.31 42.670 2.1172 2.1225 0.160 428 262 5.9 1.45 43,145 2.0950 2,1002 0.120 433 266 5.9 1.50 44,190 2.0478 2.0529 0.160 376 269 5.1 0.89 46.095 1.9675 1.9724 0.160 279 279 3.8 0.86 46.510 1.9509 1.9558 0.240 310 282 4.2 0.87 48.305 1.8826 1.8872 0.200 506 292 6.9 2.06 48.900 1.8610 1.8657 0.240 615 296 8.4 1.67 50.330 1.8115 1.8160 0.160 437 303 6.0 1.73 51.035 1.7881 1.7925 0.080 416 306 5.7 0.93 53,550 1.7099 1.7141 0.480 177 317 2.4 2.84 54,500 1.6823 1.6865 0.400 130 324 1.8 1.37 55,420 1.6565 1.6606 0.320 130 328 1.8 1.72 56,220 1.6348 1.6389 0.320 121 331 1.7 0.87 56.770 1.6203 1.6243 0.240 142 335 1.9 1.59 57,405 1.6039 1.6079 0.240 112 339 1.5 1.19 58.500 1.5764 1.5804 0.240 67 342 0.9 1.57

Manufacture of coated tablets containing flibanserin:

A) Devices used:

The following equipment was used to prepare the pharmaceutical composition according to the invention: Ekato and Ultra Turrax mixing vessel for granulating fluid and film suspension; high shear mixer / granulator (e.g. Diosna P 400);

wet sieving equipment (e.g. Alexanderwerk);

a fluid bed dryer (e.g., Glatt WSG 15);

dry sieving equipment (e.g. Quadro Comil AS197);

mixer (free fall, e.g. Servolift 120 l or tank mixer);

rotary tablet press (e.g. Fette P 1200);

coater (e.g. Glatt GC 1250);

B) Process description:

In the first step, a granulation fluid used in wet granulation was prepared. The purified water was introduced into a suitable mixing vessel and heated to a temperature of about 80 ° C. Subsequently, hypromellose (Methocel E5 Prem) and / or additional wetting binder components were added and the dispersion was cooled to room temperature. If necessary, the liquid was allowed to stand overnight (complete solution formation / reduced foaming) and mixed before use. If necessary, any weight loss was compensated by adding purified water. The dry matter (solids content) of this granulation fluid is preferably in the range 4-6%.

For the granulation process, the lactose monohydrate was finely ground and sieved, the required amount of polymorph A flibanserin (depending on the dose rate, suitably micronized) and microcrystalline cellulose (Avicel PH 101) were added in the order given, followed by mixing until homogeneity was obtained for about 4 minutes using a powered propeller stirrer. Thereafter, the granulating fluid was added by hand or using a spray nozzle and the wet mass was granulated for about 2-3 minutes, again using a powered propeller. After emptying the high shear mixer / granulator, the wet granules were wet sieved through a 3.0 mm mesh screen to get rid of large agglomerates. The wet sieved material was transferred to a conventional fluid bed dryer (or alternatively a tray dryer) and dried at an inlet air temperature of approximately 100 ° C until an outlet air temperature (or alternatively product temperature) of approximately 50 ° C (45-55 ° C) was achieved . The remaining moisture of the granulate, taking into account the loss on drying, should be 0.5-1.5%. The dried granules were then dry sieved with a Comil grind screen with a 2 mm sieve. Finally, the screened granulate is introduced into a suitable blender (free-fall), e.g. a tank mixer, cross-linked sodium carboxymethylcellulose (sodium croscarmellose, trade name: Ac-di-Sol) and magnesium stearate are added and the ingredients are mixed for 10-20 minutes. preferably for 15 minutes at a mixing speed of 10 rpm until a homogeneous mixture is obtained.

The final tableting mixture was compressed on a suitable tablet press (e.g. rotary tablet press) to obtain the appropriate target tablet weight of the required flibanserin dose rate using appropriate tools (e.g. for 50 mg tablets: 9 mm round, biconvex, bevelled edges; or for 100 mg tablets: 14 x 6.8 mm oblong shape). In order to achieve the intended drug release profile and product properties, predetermined technical requirements for the hardness of the various tools must be met.

Since the drug substance flibanserin has a bitter taste and is slightly sensitive to light, a protective coating of the tablet cores should be used to obtain a durable and consumer-friendly product. Finally, a coating suspension was prepared by filling a suitable mixing vessel with purified water and dissolving the polyethylene glycol 6000 and then the hydroxypropyl methylcellulose with a high shear mixer. In the next step, a thin aqueous suspension of titanium dioxide, talc and red iron oxide (in the case of colored coated tablets) was poured in and mixed in the film-forming polymer solution.

The dry weight of this coating suspension was 10-15%, preferably around 12-13%.

The tablet cores thus produced were loaded into a suitable coater (e.g. Accela Cota with a 36 '' receiver or Glatt GC 1250 coater with a perforated receiver and overhead spray system), and preheated to a temperature of approximately 50 ° C. After the product has reached this temperature, the coating suspension is sprayed onto the cores from one or more spray nozzles at a pressure of about 2 bar, a spray rate of about 4 kg / hour (for Accel Cota), air inlet temperature of about 60-85 ° C. It is essential to control and maintain the product temperature while spraying between 48-52 ° C to ensure high quality film coverage. Upon completion of spraying, the coated tablets were cooled to about 30 ° C and removed from the machine. The total duration of the coating process is 2-3 hours.

Following inter-process and quality control checks, the film-coated tablets were ready to be prepackaged in appropriate commercial packaging (e.g. PVC / PVDC blisters or HDPE bottles).

The following film-coated tablets were prepared in an analogous manner to that described previously.

Example No. 1. Composition

Core

Ingredients mg / tablet Polymorph A of flibanserin 25,000 Lactose Monohydrate 71,720 Microcrystalline cellulose 23.905 HPMC (Methocel E5) 1,250 Sodium carboxymethyl cellulose 2,500 Magnesium stearate 0.625

PL 211 062 B1

Cover

Ingredients mg / tablet HPMC (Methocel E5) 1.440 Polyethylene glycol 6000 0.420 Titanium dioxide 0.600 Talc 0.514 Iron oxide red 0.026

Total weight of the coated tablet 128,000 P r x l a d No 2. Composition Core Ingredients mg / tablet Polymorph A of flibanserin 50,000 Lactose Monohydrate 143,440 Microcrystalline cellulose 47.810 HPMC (e.g. Pharmacoat 606) 2,500 Sodium carboxymethyl cellulose 5,000 Magnesium stearate 1,250 Cover Ingredients mg / tablet HPMC (e.g. Pharmacoat 606) 2,400 Polyethylene glycol 6000 0.700 Titanium dioxide 1,000 Talc 0.857 Iron oxide red 0.043

Total weight of the coated tablet 255,000 P r x l a d No 3. Composition Core Ingredients mg / tablet Polymorph A of flibanserin 100,000 Lactose Monohydrate 171.080 Microcrystalline cellulose 57.020 HPMC (e.g. Methocel E5) 3,400 Sodium carboxymethyl cellulose 6,800 Magnesium stearate 1,700

Cover

Ingredients mg / tablet 1 2 HPMC (e.g. Methocel E5) 3.360 Polyethylene glycol 6000 0.980 Titanium dioxide 1,400

PL 211 062 B1 cont. further

1 2 Talc 1,200 Iron oxide red 0.060

Total weight of the coated tablet 347,000

Example No. 4. Composition Core

Ingredients mg / tablet Polymorph A of flibanserin 2,000 Dibasic calcium phosphate, anhydrous 61.010 Microcrystalline cellulose 61.010 HPMC (Methocel E5) 1.950 Sodium carboxymethyl cellulose 2,600 Colloidal silicon dioxide 0.650 Magnesium stearate 0.780

Cover

Ingredients mg / tablet HPMC (Methocel E5) 1.440 Polyethylene glycol 6000 0.420 Titanium dioxide 0.600 Talc 0.514 Iron oxide red 0.026

Total weight of the coated tablet 133,000

Example No. 5. Composition Core

Ingredients mg / tablet Polymorph A of flibanserin 100.00 Dibasic calcium phosphate, anhydrous 69.750 Microcrystalline cellulose 69.750 HPMC (e.g. Methocel E5) 2,750 Sodium carboxymethyl cellulose 5,000 Colloidal silicon dioxide 1,250 Magnesium stearate 1,500

Cover

Ingredients mg / tablet HPMC (e.g. Methocel E5) 2,400 Polyethylene glycol 6000 0.700 Titanium dioxide 1.043 Talc 0.857

Total weight of the coated tablet 255,000

PL 211 062 B1

Example No. 6. Composition Core

Ingredients mg / tablet Polymorph A of flibanserin 20,000 Lactose Monohydrate 130,000 Microcrystalline cellulose 43,100 Hydroxypropyl cellulose (e.g. Klucel LF) 1.900 Sodium starch glycolate 4,000 Magnesium stearate 1,000

Cover

Ingredients mg / tablet HPMC (e.g. Methocel E5) 2,400 Polyethylene glycol 6000 0.700 Titanium dioxide 1.043 Talc 0.857

Total weight of the coated tablet 205,000

Claims (12)

Patent claims A pharmaceutical composition for oral administration, comprising flibanserin, characterized in that it comprises a tablet core containing polymorph A of flibanserin, showing an endothermic maximum at 161 ° C as determined by DSC, in admixture with at least one pharmaceutically acceptable excipient, and further comprising a film coating the tablet core, containing titanium dioxide and / or talc. 2. A pharmaceutical composition according to claim 1 6. The composition of claim 1, wherein titanium dioxide is present in an amount of 5-55% by weight based on the total weight of the film coating the tablet. 3. A pharmaceutical composition according to claim 1 6. The method of claim 1 or 2, characterized in that the titanium dioxide is present in an amount of 5-50% by weight, based on the total weight of the film coating the tablet. 4. A pharmaceutical composition according to any one of claims 1 to 5; A method according to any of the preceding claims, characterized in that the pharmaceutically acceptable excipient is a filler selected from the group consisting of lactose monohydrate, and both finely ground material and modified lactose, such as spray dried lactose and agglomerated lactose (Tablettose), anhydrous lactose, microcrystalline cellulose , dibasic calcium phosphate, corn starch, sugar alcohols, and mixtures thereof. 5. A pharmaceutical composition according to any one of claims 1 to 5; The pharmaceutical composition according to any of the claims 1-4, characterized in that the polymorph A of flibanserin is present in amounts of 1 to 50% by weight based on the total weight of the core. 6. A pharmaceutical composition according to any one of claims 1 to 6 The composition of 1-5, characterized in that the core contains a filler in an amount of 50 to 99% by weight, based on the total weight of the core. 7. A pharmaceutical composition according to any one of claims 1-7 A composition according to any of the claims 1-6, characterized in that the core further comprises a binder selected from the group consisting of povidone, copovidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, corn starch, and mixtures thereof. 8. A pharmaceutical composition according to any one of claims 1 to 8. The composition of any of the claims 1-7, characterized in that the core further comprises a disintegrant selected from sodium starch glycolate, crospovidone, croscarmellose sodium, sodium carboxymethyl cellulose, dried corn starch, and mixtures thereof. PL 211 062 B1 9. A pharmaceutical composition according to any one of claims 1 to 9 A composition according to any of the claims 1-8, characterized in that the core further comprises antistatic agents, lubricants and release modulating agents, or anti-adhesives selected from the group consisting of silicon dioxide, talc, magnesium stearate, and mixtures thereof. 10. A pharmaceutical composition according to any one of claims 1 to 10. A film according to any of the claims 1-9, characterized in that the core coating film comprises at least one film former selected from hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, and polyethyl acrylate / methyl methacrylate. 11. Use of a pharmaceutical composition according to any one of claims 1 to 11 1-10, for the manufacture of a medicament for the treatment of diseases selected from the group consisting of depression, schizophrenia, Parkinson's disease, anxiety, sleep disorders, sexual and mental disorders, and age-related memory disorders. 12. Use according to p. 11. The method of claim 11, wherein the disease is Low Sex Drive Disorder.